Project Summary A large body of indirect evidence now strongly supports the idea that the nociceptive sensory pathway that innervates the intracranial meninges (the trigeminovascular system) is involved in the generation of some types of clinically occurring headaches, including migraine. The basic properties of this sensory pathway have been studied in detail in animal studies, but it is not yet well understood how this pathway becomes activated during a clinically occurring headache attack. One leading line of research has provided evidence in support of the CSD (cortical spreading depression) theory of migraine, including the recent findings of trigeminovascular neuron activation following CSD induction in animals. However, the study of CSD in migraine patients is necessarily somewhat anecdotal because CSD cannot be detected by routine methods in humans, and so it is not known how often it occurs, or what causes it to arise spontaneously. As a new avenue to further explore the mechanisms that can trigger headache and the potential role of cortical pathophysiology, we now propose to examine mechanisms of trigeminovascular neuron activation in an animal model of a common type of cortical pathophysiology that is well described and intensively studied in humans: cortical seizure. Based on the clinical observation that seizures are commonly followed by headache with features similar to migraine, we hypothesize that seizure can produce activation of the trigeminovascular system. We therefore propose to test this hypothesis, and to use seizure as a model to further investigate the mechanisms by which cortical processes can influence the trigeminovascular system, in the following Aims: (1) Employing single-unit recording to monitor changes in activity of first-order dura-sensitive neurons in the trigeminal ganglion, we will test the hypothesis that chemically-induced seizures can induce activation and/or sensitization of dural nociceptors. Seizure-induced effects will also be examined in trigeminal ganglion neurons that do not innervate the dura. (2) Using single-unit recording, changes in activity of second-order dural-responsive neurons in the superficial and deep laminae of the upper cervical and medullary dorsal horn will be examined following seizures in anesthetized rats. As in Aim 1, neurons that lack a dural response will also be studied. Data analysis will determine the latency, duration, and magnitude of changes in activity induced by seizure, and compare the seizure effects in dura-sensitive vs. dura-insensitive neurons. Experiments will test the hypothesis that neuronal activation will be produced by focal seizure in occipital but not parietal cortical sites, paralleling the regionally selective pattern found for the occurrence of postictal headache. In order to determine whether the seizure-induced discharge originates in terminals within the dural receptive field, lidocaine will be applied to the dura either prior to seizure induction or following seizure induction during the period of peak seizure- induced discharge.